2',3'-DIDEOXYCYTIDINE ALTERS CALCIUM BUFFERING IN CULTURED DORSAL-ROOT GANGLION NEURONS

Mitochondria play a prominent role in shaping intracellular calcium co ncentration ([Ca2+](i)) transients in dorsal root ganglion neurons. Mi tochondrial DNA polymerase is inhibited by antiviral compounds such as 2',3'-dideoxycytidine (ddC). Here, we test the hypothesis that ddC ca n alter mitochondrially mediated Ca2+ buffering in neurons. Chronic tr eatment of dorsal root ganglion cultures with ddC (7 mu M) lowered mit ochondrial DNA levels and decreased the mitochondrially mediated compo nent of depolarization-induced [Ca2+](i) transients. The inhibition in creased in a time-dependent manner, reaching a maximum at 6 days. ddC did not affect small, action potential-evoked, [Ca2+](i) transients th at are predominantly buffered by Ca2+-ATPases, suggesting that ATP lev els were not depleted. The drug did not inhibit whole-cell Ca2+ curren ts, indicating that the Ca2+ load was not affected. Thus, ddC produces a graded, time-dependent inhibition of mitochondrial function that is reflected, in part, by a decrease in the direct buffering of Ca2+ by mitochondria. This effect may contribute to the peripheral neuropathy that results from ddC treatment. Furthermore, ddC promises to be a use ful tool to study the role of mitochondria in [Ca2+](i) homeostasis an d neurodegenerative processes.